The perception of the human body as a single, self-contained organism is undergoing a paradigm shift. With the advent of 16S rRNA sequencing and metagenomics, it has become clear that humans are perhaps better understood as a supraorganism comprised of both host and microbial cells. Gut microbial populations play key roles in resistance to obesity, insulin sensitivity, glucose intolerance, cardiovascular health, an protection from colon cancer and inflammatory bowel disorders. Additionally, diet is a major modulator of gut microbial community composition and metabolism. Dietary starches and fibers that are not absorbed by the host are a major source of carbon and energy for gut bacteria. These microbes have evolved complex mechanisms to break down and metabolize such substrates, thereby vastly expanding the metabolic repertoire of the host. Gut bacteria produce a number of metabolites that are measureable in host plasma, including the short-chain fatty acids acetate, propionate, and butyrate. Many histone modifying enzyme complexes are known to be exquisitely sensitive to small-molecule metabolite levels and are thought to sense and integrate metabolic signals in response to changes in environment. An octamer of histone proteins forms the core of the eukaryotic nucleosome, a nucleoprotein structure around which ~147bp of DNA wraps to ultimately form highly compacted chromatin. Chromatin can exist in either an open or closed state, depending on the modifications present on histone proteins. Histone acetylation is generally associated with open chromatin and transcriptional activation, whereas Histone H3 lysine 27 trimethylation is associated with closed chromatin and transcriptional silencing. Therefore, is it likely that gut microbial metabolites, as a function of host diet, play a regulatory role at the level of chromatin in a variety of host tissues, not limitd solely to the gut, ultimately affecting host transcriptional programming and overall phenotype. However, the relationship between gut microbial metabolites and host chromatin remains unknown. The primary goal of the proposed work is to establish a link between gut microbial metabolism and host epigenetic programming in a variety of host tissues. A secondary goal of this work is to harness the nutritional sensitivity of gut microbiota to elucidate the effects of det on these microbial metabolite-mediated epigenetic changes, and to determine causal relationships between gut microbial metabolites and host chromatin. The specific aims are to (1) establish a link between gut microbiota and the host epigenome, (2) determine the effects of diet and microbial community composition on the host epigenome, and (3) determine causal relationships between gut microbial metabolites and host epigenetic changes. The insight gained here will guide follow-up studies to identify specific chromatin complexes that directly respond to bacterial metabolites and alter specific chromatin loci. In light of the global diet-induced obesity epidemic, this work will make key connections between host nutritional status, gut microbial populations, and ultimately host environmental adaptation via epigenetic regulation of transcriptional programs.